The present invention relates generally to biological sample analyzers used to perform assays of patient specimen samples. More particularly, the present invention relates to a method and system for the scheduling the operating steps for performing assays of biological samples in an automatic analyzer with reproducible and reliable performance.
Biological sample analyzers, of the type considered herein, are automated instruments that may be used in hospitals, clinics, laboratories, or other locations, to run routine tests (assays) on samples of patient specimens such as blood, spinal fluid, urine, serum, plasma, and so on. An automated analyzer of the type discussed herein includes an analyzer unit that runs tests on a number of patient specimen samples that are loaded into the unit. An operator-user prepares the samples by placing portions of the patients' specimen samples into a number of like-sized sample containers. These samples may be diluted or otherwise treated, depending upon the type of analyzer used, the type of assay being performed, and other factors. The containers are then placed in the analyzer unit. The containers may first be placed in a rack or carousel that is then placed in the analyzing unit. The rack may accommodate a number of sample containers, e.g. 24. In addition, one or more appropriate chemical reagents, needed to perform the assays, are also placed in the analyzer unit. In order to mix reagents with the samples, the analyzer unit may also include a fluid moving system, such as a robotic probe mounted on a boom, which is adapted to draw up portions of the reagents and/or samples and expel them into appropriate locations, e.g. additional cells such as reaction cells provided in the sample containers, where a reaction can take place. The analyzer unit also may include a means for detecting a reaction in the reaction cells. This may include an optical detector to observe fluorescence reactions and make optical measurements to obtain a result for each sample. The analyzer unit may also typically include other mechanical systems to move the sample containers and the probe. The analyzer unit may also provide for cleaning the probe between certain tasks in order to avoid contamination between samples. For this purpose, the analyzer unit may also include a washing station and a waste dispensing container to hold the used rinse solution.
After the operator-user loads the specimen samples, enters appropriate instructions, and starts the unit, the analyzer runs unattended. When placed in operation, the analyzer unit, using the appropriate chemical reagent, runs the same test on each of the samples in the sample containers and will perform identical operations on each of the samples loaded in the rack. When it is finished, the analyzer prints out or otherwise reports on the results of its testing.
Biological analyzers utilize different chemistries for performing assays of specimen samples. One type of assays used in biological analyzers includes immunoassays and solid phase procedures. Analyzers for performing immunoassays in general and enzyme immunoassays in particular are known in the art.
A biological analyzer that utilizes immunoassay chemistry to perform assays of specimen samples loaded therein is the IMx.RTM. analyzer introduced in 1988 by Abbott Laboratories, of North Chicago, Ill. (A description of the IMx analyzer is included in "The Abbott IMx Automated Benchtop Immunochemistry Analyzer System", by Fiore, M. et al., Clinical Chemistry, Vol. 34, No. 9, 1988, which is specifically incorporated herein by reference in its entirety). The IMx analyzer is a biological sample analyzer that has been developed for use in conjunction with solid phase immunoassay procedures to perform a variety of assays (such as sandwich and competitive assays). The IMx analyzer uses a technology referred to as microparticle capture enzyme immunoassay (MEIA) and fluorescence polarization immunoassay (FPIA). The IMx analyzer includes a microprocessor used to control a robotic arm with 2 degrees of freedom and a rotating carousel to process the samples for assay. One assay can be done on each of 24 specimen samples in 30-40 minutes or more unattended after loading (i.e. with "walk away" automation). Assay results are output to a printer or a computer interface.
A biological sample analyzer, such as the IMx analyzer described above, can execute the steps required for performing assays of up to 24 specimen samples, including the steps of counting the samples, identifying which assay to run, warming the reagents and reaction cells to appropriate temperatures, pipetting the reagents and samples, diluting samples if required, timing critical assay steps such as incubations, washing unbound conjugate, quantifying the fluorescence signal and performing data reduction to yield a useful result.
The container used for holding each of the specimen samples for a biological sample analyzer, such as the IMx analyzer, may be a disposable assay cartridge having a plurality of wells, with at least one reaction well and one separation well. The separation well may contain a fibrous matrix positioned across its entrance and an absorbent material positioned below the fibrous matrix. Microparticles react with an analyte containing sample and one or more reagents to form a complex. This complex is immobilized on the matrix of the separation cell. The excess sample and reagent are washed through the matrix and captured in the absorbent material below.
The results of the reactions may be read using known optical detection techniques. For example, using conventional solid phase procedures, an analyte can be labeled or tagged with an enzyme which in the presence of its substrate fluoresces, and emits light at a known wave length. The rate at which the fluorescent product is produced is indicative of the concentration of the analyte in the biological sample. A conventional fluorometer is suitable for illuminating the fibrous matrix with a beam of light having the appropriate excitation wave length. The fluorometer also detects the intensity of the light at the emission wave length. Assays using this type of solid phase technology has been found to provide a high degree of sensitivity.
A biological sample analyzer, such as the IMx analyzer, provides for performing assays of patients' specimen samples and reading the results of such assays in a mass production type manner. This allows such assays to be made available quickly and conveniently.
Even though such analyzers can provide significant advantages by performing assays quickly and conveniently, further advantages for the user could be obtained if the overall through put of the analyzer could be increased. One way to provide even more advantages and convenience for users of biological analyzers would be to provide the capability to perform more than one assay on the specimen samples in an unattended run. Although a biological analyzer like the IMx analyzer can perform different types of assays and can perform assays on a number of specimen samples unattended, the analyzer can run only one type of assay at a time. If a different type of assay is to be performed, the analyzer would have to be reloaded with different reagents. Also, because different types of assays may require different amounts of the sample specimen, different amounts of reagents, different processing steps, different incubation times, etc., the analyzer would also be reset at the beginning of the run to perform the new assay. In the case of the IMx analyzer, a different memory module may have to be inserted containing the instructions for the analyzer unit for performing the different assay. Thus, even if only a few of several different types of assays need to be run, the operator-user has to load and run the analyzer for the first type of assay for only a few samples and then reload the analyzer to run the second type of assay on another batch of samples using perhaps different reagents. It is recognized that for many users of the IMx analyzer, or other biological sample analyzers, it would be convenient and advantageous to be able to perform more than one type of assay during an unattended run.
Although it may be desirable to provide a biological analyzer with the capability to perform more than one assay in an unattended run, there are several obstacles that make providing this feature complicated. For example, different assays require different functions or operations to be performed upon the sample specimens in the carousel rack by the mechanical or optical systems of the analyzer. In the prior IMx analyzer, or in other analyzers in which only one type of assay is being performed during an unattended run, it can be difficult to determine when each of the operations upon each of the samples will be performed so that sufficient time allowance can be provided to ensure that incubation periods limits are not exceeded or that the samples or reagents do not evaporate. This is even more difficult in an analyzer in which the user is permitted to select the type and number of assays to be performed in an unattended run. For example, if there are 24 specimen samples in the carousel rack and the operator-user is permitted to select any one of three different assays to be performed on the samples, there are almost 2500 different permutations of possible combinations of assays and samples that the user can select. (The number is 2925 if all possible combinations, even those that an operator-user would never run are considered). If the user is permitted to select any one of four different assays to be performed on the 24 samples, there are approximately 10,000 different permutations of possible combinations. This presents an operating problem because certain tasks in the automatic analyzer must be performed on the samples at certain times or within certain specific time limits. Thus, there is a requirement to efficiently schedule the activities being performed by the automatic analyzer. Considering that 100 or more different mechanical operations can be performed on each sample, and that due to chemical reaction constraints certain operations must be performed within certain rigidly specified time durations from other operations in order to obtain valid results, it can readily be appreciated that scheduling and operating an analyzer to perform more than one assay unattended is considerably more complicated than scheduling and operating an analyzer in which only one assay is performed in an unattended run.
One automatic assay device is known having the capability to perform more than one assay on specimen samples loaded therein in an unattended (e.g. "walk-away") run. That device is the ADx.RTM. biological analyzer available from Abbott Laboratories. Although the ADx analyzer can perform more than one type of assay on samples loaded in its carousel rack, the ADx analyzer is used primarily for assays that are different than those performed by the IMx analyzer. The assays performed by the ADx analyzer are, in general, simpler and typically include fewer steps. Also with respect to the assays performed by the ADx analyzer, there are, in general, fewer constraints on incubation periods between steps. Accordingly, when the ADx biological sample analyzer is used to perform more than one assay in a run, the scheduling of the various operations to be performed by the analyzer systems on the specimen samples can be accomplished by using the minimum incubation time interval between operations. However, when the minimum incubation period is used, the throughput of the analyzer can decrease (i.e., the overall time to run the assays increases) due to conflicts among the schedules of the assays. Moreover, with the type of assays performed by the IMx, such as MEIA and FPIA, there are usually more steps for each assay and there are more constraints that certain steps must be performed within certain incubation time limits to produce valid data. Further, with the types of assays performed on the IMx analyzer, there is also greater variability in the assay steps and incubation limits between different steps among different assays. Accordingly, it is difficult to schedule an analyzer such as the IMx analyzer to perform more than one assay in an unattended run.
One of the factors affecting the scheduling of instrument operations is the variation in time that it takes to perform certain operating steps by the analyzer on the specimen samples. Such variations in operation can arise in numerous ways. One of the ways that variations can arise relates to the number of possible schedule permutations as a result of scheduling more than one assay to be performed in a run.
With an analyzer capable of performing more than one assay in a run, the number of possible permutations of load lists is high thereby complicating the scheduling of the analyzer instrument system operations to account for such variations. It can be appreciated that the functions being performed by the analyzer instrument systems involve certain mechanical operations, such as moving a boom and probe, aspirating a reagent, sample, or rinse, moving the carousel rack, "step-look" operations to find a fluid level, etc. The amount of time that these operations take is a function of the start and stop positions of the probe, the rack, the reagents, etc., and can also vary depending upon the number and location of each type of sample being run for each type of test.
For example, the movement of the carousel can take different amounts of time depending upon whether the carousel has to move only a few degrees or whether it has to move a complete half revolution. Evidently, the half rotation takes longer to perform than the movement of only a few degrees. However, when attempting to schedule the operation of the analyzer instrument systems, these variations in position are a factor and can add up over a run. Since such variations in movement time are a function of both the previous and subsequent positions of the instrument system, these variations cannot be accounted for until both all these positions are established.
Also, there may be certain variations related to training calibration points, interrupt latencies, the clock speed of the microprocessor, code running overhead, motor controller variations, etc. In addition, there may be variations between different machines due to design tolerances among machines. Also, certain analyzers may have minor idiosyncracies that affect the time that it takes to perform certain instrument system operations but that do not detract from safe reliable performance.
Although it may be technically possible to calculate a prediction that closely approximates the amount of time variations in instrument activities should take based upon the start and stop location of the instrument systems, such an effort would be burdensome and require a significant amount of processing power. Moreover, such detailed calculation might not necessarily account for the design tolerances from one analyzer to the next mentioned above or certain idiosyncracies associated with certain analyzers.
These variations in performance times can complicate the operation of the analyzer because certain assay steps such as incubation periods, must be performed within specific defined time periods of other steps to provide valid data. Because these incubation periods must be strictly observed if the analyzer completes certain instrument operations too quickly or too slowly it can exceed the required time limits.
Thus, the scheduling of the operating steps of an analyzer becomes very burdensome and complicated especially when more than one assay is being performed in an unattended run.
Accordingly, it is an object of the present invention to provide a biological analyzer that is capable of performing more than one assay on specimen samples loaded therein in an unattended run in a manner that provides reasonable through put.
It is a further object to provide a biological analyzer that accounts for variations in instrument system movements and locations, machine tolerance variations and other factors and provides a reliable and reproducibly consistent assay performance.